DE68917211T2 - N- (5,6,7,8-tetrahydropyrido (2,3-d) pyrimidin-6-ylalkanoyl) glutamic acid derivatives. - Google Patents
N- (5,6,7,8-tetrahydropyrido (2,3-d) pyrimidin-6-ylalkanoyl) glutamic acid derivatives.Info
- Publication number
- DE68917211T2 DE68917211T2 DE68917211T DE68917211T DE68917211T2 DE 68917211 T2 DE68917211 T2 DE 68917211T2 DE 68917211 T DE68917211 T DE 68917211T DE 68917211 T DE68917211 T DE 68917211T DE 68917211 T2 DE68917211 T2 DE 68917211T2
- Authority
- DE
- Germany
- Prior art keywords
- pyrimidin
- tetrahydropyrido
- hydroxy
- glutamic acid
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000002306 glutamic acid derivatives Chemical class 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 125000006239 protecting group Chemical group 0.000 claims abstract description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 7
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- 150000002431 hydrogen Chemical class 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229960002989 glutamic acid Drugs 0.000 claims description 41
- -1 2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 39
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- 239000002253 acid Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 5
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- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
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- 108090000790 Enzymes Proteins 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
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- 239000000292 calcium oxide Substances 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- JZYKFLLRVPPISG-UHFFFAOYSA-N hex-5-ynenitrile Chemical compound C#CCCCC#N JZYKFLLRVPPISG-UHFFFAOYSA-N 0.000 description 1
- VPFMEXRVUOPYRG-UHFFFAOYSA-N hex-5-ynoic acid Chemical compound OC(=O)CCCC#C VPFMEXRVUOPYRG-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- OUMGIYIBWRLOAF-UHFFFAOYSA-N n,n-dimethylpyrimidin-2-amine Chemical compound CN(C)C1=NC=CC=N1 OUMGIYIBWRLOAF-UHFFFAOYSA-N 0.000 description 1
- YWBHXANUFSSMNL-UHFFFAOYSA-N n-(6-bromo-4-oxo-1h-pyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide Chemical compound C1=C(Br)C=NC2=NC(NC(=O)C(C)(C)C)=NC(O)=C21 YWBHXANUFSSMNL-UHFFFAOYSA-N 0.000 description 1
- KLUNIYXWSVXRCD-UHFFFAOYSA-N n-(6-ethynyl-4-oxo-1h-pyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide Chemical compound C1=C(C#C)C=NC2=NC(NC(=O)C(C)(C)C)=NC(O)=C21 KLUNIYXWSVXRCD-UHFFFAOYSA-N 0.000 description 1
- 208000025440 neoplasm of neck Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940127075 other antimetabolite Drugs 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- SJLOMQIUPFZJAN-UHFFFAOYSA-N oxorhodium Chemical compound [Rh]=O SJLOMQIUPFZJAN-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 229910003450 rhodium oxide Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical compound OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrane Compounds (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft die einzelnen Diastereomere und das diastereomere Gemisch von Glutaminsäurederivaten der Formel: The present invention relates to the individual diastereomers and the diastereomeric mixture of glutamic acid derivatives of the formula:
in der:in the:
R¹ -OH oder -NH&sub2; darstellt;R¹ represents -OH or -NH₂;
R² Wasserstoff oder eine Carboxylschutzgruppe darstellt:R² represents hydrogen or a carboxyl protecting group:
R³ eine Kohlenstoff-Kohlenstoffbindung, ein Alkylen mit 1 bis 4 Kohlenstoffatomen, Cyclohexylen, oder R³ is a carbon-carbon bond, an alkylene having 1 to 4 carbon atoms, cyclohexylene, or
darstellt;represents;
R&sup4; Wasserstoff oder eine Aminoschutzgruppe darstellt;R⁴ represents hydrogen or an amino protecting group;
Q -S- oder -O- darstellt;Q represents -S- or -O-;
R&sup5; Wasserstoff, Chlor oder Fluor darstellt; undR⁵ represents hydrogen, chlorine or fluorine; and
die Konfiguration um das mit * gekennzeichnete Kohlenstoffatom S ist.the configuration around the carbon atom marked with * is S.
Die Verbindungen der Formeln IA und IB besitzen einen inhibitorischen Effekt auf ein oder mehrere Enzyme, die Folsäure, und im besonderen metabolische Derivate der Folsäure, als Substrat verwenden. Die Verbindungen können somit, allein oder in Kombination, verwendet werden, um das Wachstum von solchen Neoplasmen zu inhibieren, die ansonsten von den so inhibierten Enzymen abhängig sind.The compounds of formulas IA and IB have an inhibitory effect on one or more enzymes, folic acid, and in particular metabolic derivatives of folic acid, as a substrate. The compounds can thus be used, alone or in combination, to inhibit the growth of neoplasms that are otherwise dependent on the enzymes so inhibited.
Die Erfindung betrifft auch die pharmazeutisch akzeptablen Salze der Verbindungen der Formeln IA und IB, die Verfahren zur Herstellung dieser Verbindungen und ihrer Salze sowie pharmazeutische Zusammenensetzungen, die diese Verbindungen oder ihre Salze enthalten.The invention also relates to the pharmaceutically acceptable salts of the compounds of formulas IA and IB, the processes for preparing these compounds and their salts, and pharmaceutical compositions containing these compounds or their salts.
Der Ausdruck Alkylen, so wie er hier Verwendung findet, bedeutet eine gerade oder verzweigte zweiwertige aliphatische Gruppe von 1 bis 4 Kohlenstoffatomen, die Methylen, Ethylen, Trimethylen, Tetramethylen, 1,1-Propyliden, 2,2-Propyliden, 1,2-Propandiyl, 2,3-Butandiyl usw. einschließt. In analoger Weise bedeutet Cyclohexylen eine divalente Cycloalkangruppe mit 6 Kohlenstoffatomen, die 1,2-Cyclohexylen, 1,3-Cyclohexylen und 1,4-Cyclohexylen einschließt.The term alkylene as used herein means a straight or branched divalent aliphatic group of 1 to 4 carbon atoms which includes methylene, ethylene, trimethylene, tetramethylene, 1,1-propylidene, 2,2-propylidene, 1,2-propanediyl, 2,3-butanediyl, etc. Analogously, cyclohexylene means a divalent cycloalkane group of 6 carbon atoms which includes 1,2-cyclohexylene, 1,3-cyclohexylene and 1,4-cyclohexylene.
Die Schutzgruppen, die als R² und R&sup4; gekennzeichnet sind und hierin Verwendung finden, bedeuten Gruppen, die im allgemeinen nicht in den endgültigen therapeutischen Verbindungen vorhanden sind, die aber absichtlich während eines Teils der Synthese eingeführt werden, um eine Gruppe zu schützen, die ansonsten im Verlauf der chemischen Manipulationen reagieren könnte, und die danach zu einem späteren Zeitpunkt der Synthese wieder entfernt werden. Da somit Verbindungen, die solche Schutzgruppen tragen, in erster Linie als chemische Zwischenstufen von Bedeutung sind (obwohl einige Derivate ebenfalls biologische Aktivität zeigen), ist ihre genaue Struktur nicht kritisch. Zahlreiche Reaktionen für die Bildung und Entfernung solcher Schutzgruppen sind in einer Anzahl von Standardwerden beschrieben, einschließlich, zum Beispiel, "Protective Groups in Organic Chemistry", Plenum Press, London und New York, 1973; Greene, Th. W. "Protective Groups In Organic Synthesis", Wiley, New York, 1981; "The Peptides", Vol. I, Schröder und Lubke, Academic Press, London und New York, 1965; Methoden der organischen Chemie", Houben-Weyl, 4. Auflage, Vol.15/I, Georg Thieme Verlag, Stuttgart 1974.The protecting groups designated R² and R⁴ as used herein represent groups which are not generally present in the final therapeutic compounds, but which are deliberately introduced during part of the synthesis to protect a group which might otherwise react during the course of the chemical manipulations, and which are subsequently removed at a later stage of the synthesis. Thus, since compounds bearing such protecting groups are primarily of importance as chemical intermediates (although some derivatives also exhibit biological activity), their precise structure is not critical. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard references, including, for example, "Protective Groups in Organic Chemistry", Plenum Press, London and New York, 1973; Greene, Th. W. "Protective Groups In Organic Synthesis", Wiley, New York, 1981; "The Peptides", Vol. I, Schröder and Lubke, Academic Press, London and New York, 1965; Methods of Organic Chemistry", Houben-Weyl, 4th edition, Vol.15/I, Georg Thieme Verlag, Stuttgart 1974.
Eine Carboxylgruppe kann als eine Estergruppe geschützt werden, die selektiv unter ausreichend milden Bedingungen, um die gewünschte Struktur des Moleküls nicht zu zerstören, wieder entfernt werden kann, besonders als ein niederer Alkylester, wie zum Beispiel Methyl oder Ethyl, und im besonderen als ein Ester, welcher an der 1-Position verzweigt ist, wie zum Beispiel t.-Butyl; und als ein solcher niederer Alkylester, der in der 1- oder 2-Position mit (i) einer niederen Alkoxygruppe, wie zum Beispiel Methoxymethyl, 1 Methoxyethyl und Ethoxymethyl, (ii) einer niederen Alkylthiogruppe, wie zum Beispiel Methylthiomethyl und 1-Ethylthioethyl; (iii) einer Halogengruppe, wie zum Beispiel 2,2,2-Trichlorethyl, 2-Bromethyl und 2-Iodethoxycarbonyl; (iv) einer oder zwei Phenylgruppen, von denen jede unsubstituiert oder mono-, di- oder trisubstituiert sein kann mit, zum Beispiel, einer niederen Alkylgruppe, wie zum Beispiel tert.-Butyl, einer niederen Alkoxygruppe, wie zum Beispiel Methoxy, Hydroxy, Halogen, wie zum Beispiel Chlor, und Nitro, wie zum Beispiel Benzyl, 4-Nitrobenzyl, Diphenylmethyl, Di-(4-Methoxyphenyl)methyl; oder (v) einer Aroylgruppe, wie zum Beispiel Phenacyl, substituiert ist. Eine Carboxylgruppe kann auch in der Form einer organischen Silylgruppe, wie zum Beispiel als trisubstituierte niedere Alkylsilylgruppe, wie zum Beispiel Trimethylsilyloxycarbonyl, geschützt werden.A carboxyl group can be protected as an ester group which can be selectively removed under sufficiently mild conditions not to destroy the desired structure of the molecule, particularly as a lower alkyl ester such as methyl or ethyl, and in particular as an ester branched at the 1-position such as t-butyl; and as such a lower alkyl ester branched at the 1- or 2-position with (i) a lower alkoxy group such as methoxymethyl, 1-methoxyethyl and ethoxymethyl, (ii) a lower alkylthio group such as methylthiomethyl and 1-ethylthioethyl; (iii) a halogen group such as 2,2,2-trichloroethyl, 2-bromoethyl and 2-iodoethoxycarbonyl; (iv) one or two phenyl groups, each of which may be unsubstituted or mono-, di- or tri-substituted with, for example, a lower alkyl group such as tert-butyl, a lower alkoxy group such as methoxy, hydroxy, halogen such as chloro, and nitro such as benzyl, 4-nitrobenzyl, diphenylmethyl, di-(4-methoxyphenyl)methyl; or (v) an aroyl group such as phenacyl. A carboxyl group may also be protected in the form of an organic silyl group such as a trisubstituted lower alkylsilyl group such as trimethylsilyloxycarbonyl.
Aminogruppen können in ähnlicher Weise als ein Amid unter Verwendung einer Acylgruppe geschützt werden, die selektiv unter milden Bedingungen wieder entfernt werden kann, besonders Formyl, einer niedere Alkanoylgruppe, die an der 1-Position verzweigt ist, insbesondere einer tertiären Alkanoylgruppe wie zum Beispiel Pivaloyl, oder einer niederen Alkanoylgruppe, die in der 1-Position mit z.Bsp. Trifluoracetyl substituiert ist.Amino groups can be protected in a similar manner as an amide using an acyl group which can be selectively removed under mild conditions, particularly formyl, a lower alkanoyl group branched at the 1-position, particularly a tertiary alkanoyl group such as pivaloyl, or a lower alkanoyl group substituted at the 1-position with e.g. trifluoroacetyl.
Eine erste Gruppe mit bevorzugten Verbindungen ist diejenige, worin R¹ -OH darstellt und sowohl R² als auch R&sup4; Wasserstoff darstellen. Eine erste bevorzugte Untergruppe innerhalb dieser Gruppe ist diejenige, in der R³ eine Kohlenstoff- Kohlenstoffbindung, Methylen, Ethylen, Trimethylen, Tetramethylen oder 1,4-Cyclohexylen darstellt. Bevorzugte Spezies innerhalb dieser Untergruppe schließen die (R, S) und (S, S) Diastereomere von N-[3-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)propionyl]-L- glutaminsäure; N-[4-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)butyryl]-L- glutaminsäure; N-[5-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)pentanoyl]-L- glutaminsäure; N-[6-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)hexanoyl]-L- glutaminsäure; N-[7-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)heptanoyl]-L- glutaminsäure; und N-[4-(2-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl)cyclohex-1- ylcarbonyl]-L-glutaminsäure ein.A first group of preferred compounds is that in which R¹ is -OH and both R² and R⁴ are hydrogen. A first preferred subgroup within this Group is that in which R³ represents a carbon-carbon bond, methylene, ethylene, trimethylene, tetramethylene or 1,4-cyclohexylene. Preferred species within this subgroup include the (R,S) and (S,S) diastereomers of N-[3-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)propionyl]-L-glutamic acid; N-[4-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L-glutamic acid; N-[5-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl]-L-glutamic acid; N-[6-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)hexanoyl]-L-glutamic acid; N-[7-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)heptanoyl]-L-glutamic acid; and N-[4-(2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl)cyclohex-1-ylcarbonyl]-L-glutamic acid.
Eine zweite bevorzugte Unterklasse sind diejenigen Verbindungen, in denen R³: A second preferred subclass are those compounds in which R³:
darstellt, wobei R&sup5; Wasserstoff und Q -S- darstellen. Bevorzugte Spezies in dieser Untergruppe schließen die (R, S) und (S, S) Diastereomere von N-[5-(2-{2-Amino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2- ylcarbony]-L-glutaminsäure; N-[5-(4-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbony]- L-glutaminsäure; N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]- L-glutaminsäure; N-[4-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]- L-glutaminsäure; N-[3-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbony]- L-glutaminsäure; N-[2-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]- L-glutaminsäure; und N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)fur-2-ylcarbony]-L- glutaminsäure ein.where R5 is hydrogen and Q is -S-. Preferred species in this subgroup include the (R,S) and (S,S) diastereomers of N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbony]-L-glutamic acid; N-[5-(4-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbony]-L-glutamic acid; N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]-L-glutamic acid; N-[4-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]- L-glutamic acid; N-[3-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbony]- L-glutamic acid; N-[2-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbony]- L-glutamic acid; and N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)fur-2-ylcarbony]-L- glutamic acid.
Die Verbindungen der vorliegenden Erfindung können oft vorteilhafterweise in der Form eines pharmazeutisch akzeptablen Salzes angewendet werden. Diese Formen, einschließlich deren Hydrate, sind oft kristallin und für die Herstellung von Lösungen oder der Formulierung von pharmazeutischen Zusammensetzungen von Vorteil. Pharmazeutisch akzeptable Salze und Basen schließen jene ein, die aus Alkalimetallen, Erdalkalimetallen, nicht-toxischen Metallen, Ammonium, sowie mono-, di- und trisubstituierten Aminen gebildet werden, wie zum Beispiel Natrium-, Kalium-, Lithium-, Calcium-, Magnesium-, Aluminium-, Zink-, Ammonium-, Trimethylammonium-, Triethanolammonium-, Pyridinium- und substituierte Pyridiniumsalze. Vorteilhaft sind die Mono- und Dinatriumsalze, besonders das Dinatriumsalz.The compounds of the present invention can often be advantageously employed in the form of a pharmaceutically acceptable salt. These forms, including hydrates thereof, are often crystalline and are advantageous for preparing solutions or formulating pharmaceutical compositions. Pharmaceutically acceptable salts and bases include those formed from alkali metals, alkaline earth metals, non-toxic metals, ammonium, and mono-, di- and tri-substituted amines such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethanolammonium, pyridinium and substituted pyridinium salts. Advantageous are the mono- and disodium salts, especially the disodium salt.
Die Verbindungen dieser Erfindung, in denen R³ Alkylen oder The compounds of this invention in which R³ is alkylene or
ist, können durch katalytische Hydrierung einer Verbindung der Formel: can be prepared by catalytic hydrogenation of a compound of the formula:
hergestellt werden, in derare manufactured in the
Z¹ und Z², einzeln genommen, jeweils Wasserstoff darstellen oder zusammen genommen eine Kohlenstoff-Kohlenstoffbindung darstellen;Z¹ and Z², taken individually, each represent hydrogen or taken together represent a carbon-carbon bond ;
R¹ wie hierin definiert ist;R¹ is as defined herein;
R²' eine Carboxylschutzgruppe darstellt;R²' represents a carboxyl protecting group;
R³' ein Alkylen mit Kohlenstoff-Kohlenstoffbindung aus 1 bis 4 Kohlenstoffatomen, oder R³' is an alkylene with carbon-carbon bonds of 1 to 4 carbon atoms, or
darstelltrepresents
undand
R&sup4;' eine Aminoschutzgruppe darstellt.R⁴ represents an amino protecting group.
Geeignete Katalysatoren für die Hydrierung schließen Edelmetalle und Edelmetalloxide, wie zum Beispiel Palladium- oder Platinoxid, Rhodiumoxid, und die vorangehenden auf einem Träger wie Kohlenstoff oder Calciumoxid ein.Suitable catalysts for the hydrogenation include noble metals and noble metal oxides such as palladium or platinum oxide, rhodium oxide, and the foregoing on a support such as carbon or calcium oxide.
Es wird ein Gemisch aus Diastereomeren der Formeln IA und IB erhalten, in der R²' eine Carboxylschutzgruppe und R&sup4;' eine Aminoschutzgruppe darstellen. Diese Schutzgruppen können dann durch saure oder basiche Hydrolyse, wie zum Beispiel mit Natriumhydroxid, entfernt werden, um Verbindungen der Formel I zu erhalten, in der sowohl R² als auch R&sup4; Wasserstoff darstellen.A mixture of diastereomers of formulas IA and IB is obtained in which R²' is a carboxyl protecting group and R⁴ is an amino protecting group. These protecting groups can then be removed by acidic or basic hydrolysis, such as with sodium hydroxide, to obtain compounds of formula I in which both R² and R⁴ are hydrogen.
Verbindungen der Formel II können durch Verwendung analoger Verfahren zu denen, die in der Europäischen Patentanmeldung Nr. 87308921.3. beschrieben sind, hergestellt werden. Auf diese Art wird in einer ersten Ausführungsform eine Verbindung der Formel: Compounds of formula II can be prepared using analogous procedures to those described in European Patent Application No. 87308921.3. In this way, in a first embodiment, a compound of formula:
in der X Brom oder Iod darstellt und R&sup4;' wie hierin definiert ist, mit einer ungesättigten Verbindung der Formel: in which X is bromine or iodine and R⁴ is as defined herein, with an unsaturated compound of the formula:
in der Z¹, Z², R²' und R³' wie hierin beschrieben sind, in Gegenwart eines Palladium/trisubstituiertem Phosphin- Katalysators, der von dem Typ ist, der von Sakamoto, Synthesis, 1983, 312 et seq., beschrieben ist, zur Reaktion gebracht.in which Z¹, Z², R²' and R³' are as described herein, in the presence of a palladium/trisubstituted phosphine catalyst which is of the type described by Sakamoto, Synthesis, 1983, 312 et seq.
Die Verbindungen dieser Erfindung, in denen R³ Cyclohexylen darstellt, können durch anfängliche katalytische Hydrierung einer Verbindung mit der Formel: The compounds of this invention wherein R³ is cyclohexylene can be prepared by initial catalytic hydrogenation of a compound having the formula:
hergestellt werden, in der R&sup4;' eine Aminoschutzgruppe darstellt und R¹ wie hierin beschrieben ist. Verbindungen der Formel V, in denen R¹ -OH darstellt, werden in analoger Weise zu den Verfahren, die in der Europäischen Patentanmeldung Nr. 87308921.3 beschrieben sind, und die korrespondierenden Verbindungen, in denen R¹ NH&sub2; darstellt, werden daraus in der oben beschriebenen Art und Weise hergestellt.in which R⁴ represents an amino protecting group and R¹ is as described herein. Compounds of formula V in which R¹ represents -OH are prepared in an analogous manner to the processes described in European Patent Application No. 87308921.3 and the corresponding compounds in which R¹ represents NH₂ are prepared therefrom in the manner described above.
Geeignete Katalysatoren für die Hydrierung der Verbindungen der Formel V schließen Edelmetalle und Edelmetalloxide ein, wie zum Beispiel Palladium- oder Platinoxid. Auf diese Weise wird eine Verbindung der Formel: Suitable catalysts for the hydrogenation of the compounds of formula V include noble metals and noble metal oxides, such as palladium or platinum oxide. In this way, a compound of the formula:
erhalten.receive.
Verbindungen der Formel VI werden dann mit einem geschützten Glutaminsäurederivat der Formel: Compounds of formula VI are then treated with a protected glutamic acid derivative of the formula:
verbunden,tied together,
in der R²' eine Carboxylschutzgruppe darstellt, in der Weise, die im allgemeinen in der PCT Anmeldung WO 86/05181 beschreiben ist, unter Anwendung herkömmlicher Kondensationsverfahren zur Herstellung der Peptidbindungen, wie zum Beispiel der Aktivierung der Carboxylgruppe durch Bildung eines gemischten Anhydrids, Behandlung mit DCC oder der Verwendung von Diphenylchlorphosphonat. Die Schutzgruppen, die durch R²' und R&sup4;' dargestellt sind, werden in der gleichen wie oben beschriebenen Weise entfernt.in which R²' represents a carboxyl protecting group, in the manner generally described in PCT application WO 86/05181, using conventional condensation techniques to prepare the peptide bonds, such as activation of the carboxyl group by formation of a mixed anhydride, treatment with DCC or use of diphenyl chlorophosphonate. The protecting groups represented by R²' and R⁴ are removed in the same manner as described above.
In einer dritten Ausführungsform können Verbindungen der Formel II unter Verwendung analoger Verfahren zu denen, die in der Europäischen Patentanmeldung Nr. 87308921.3. beschreiben sind, hergestellt werden. Auf diese Art wird eine ungesättigte Verbindung der Formel: In a third embodiment, compounds of formula II can be prepared using analogous procedures to those described in European Patent Application No. 87308921.3. In this way, an unsaturated compound of formula:
in der Z¹, Z² und R&sup4;' wie hierin beschrieben sind, mit einer Verbindung der Formel: in which Z¹, Z² and R⁴ are as described herein, with a compound of the formula:
in der X Brom oder Iod darstellt und R²', R&sup5;' und Q wie hierin definiert sind, in Gegenwart eines Palladium/trisubstituierten Phosphin-Katalysators, der von dem Typ ist, der von Sakamoto, Synthesis, 1983, 312 et seq., beschrieben ist, zur Reaktion gebracht.in which X is bromine or iodine and R²', R⁵' and Q are as defined herein, in the presence of a palladium/trisubstituted phosphine catalyst of the type described by Sakamoto, Synthesis, 1983, 312 et seq.
Es wird entsprechend des vorhergehenden Verfahrens eine Verbindung der Formel II erhalten, in der R¹' -OH darstellt. Wenn eine Verbindung gewünscht wird, in der R¹' -NH2 darstellt, kann dieses Produkt mit 1,2,4-Triazol und (4- Chlorphenyl)dichlorphosphat behandelt werden und das Produkt dieser Reaktion kann dann mit konzentriertem Ammonium behandelt werden.A compound of formula II is obtained according to the previous procedure in which R¹' represents -OH. If a compound in which R¹' represents -NH2 is desired, this product can be treated with 1,2,4-triazole and (4-chlorophenyl)dichlorophosphate and the product of this reaction can then be treated with concentrated ammonium.
Verbindungen der Formel IX werden durch Verbinden einer Verbindung mit der Formel: Compounds of formula IX are prepared by combining a compound of the formula:
in der X, R&sup5; und Q wie hierin definiert sind, mit einem geschützten Glutaminsäurederivat der Formel VII in der gleichen wie oben beschriebenen Art und Weise unter Anwendung herkömmlicher Kondensationsverfahren zur Herstellung von Peptidbindungen hergestellt.in which X, R⁵ and Q are as defined herein, with a protected glutamic acid derivative of formula VII in the same manner as described above using conventional condensation techniques for preparing peptide bonds.
Das Gemisch der einzelnen, durch die Formeln IA und IB dargestellten Diastereomere kann als solches therapeutisch eingesetzt werden oder kann mechanisch, zum Beispiel durch Chromatographie, aufgetrennt werden. Als andere Möglichkeit können die einzelnen Diastereomere getrennt werden durch Bildung von diastereomeren Salzen mit einer chiralen Säure, wie zum Beispiel den einzelnen Enantiomeren der 10- Kampfersulfonsäure, Kampfersäure, alpha-Bromkampfersäure, Methoxyessigsäure, Weinsäure, Diacetyltartarsäure, Äpfelsäure, Pyrrolidon-5-carboxylsäure und dergleichen, und dann durch Freisetzung einer oder beider der einzelnen diastereomeren Basen, wahlweise durch Wiederholung des Prozesses, um entweder eine oder beide im wesentlichen frei von der anderen zu erhalten; d.h. in einer Form zu erhalten mit einer optischen Reinheit von > 95%. Diese Trennung kann vor oder nach der Entfernung jeder beliebigen Schutzgruppe durchgeführt werden.The mixture of the individual diastereomers represented by formulas IA and IB can be used therapeutically as such or can be separated mechanically, for example by chromatography. Alternatively, the individual diastereomers can be separated by forming diastereomeric salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid and the like, and then releasing one or both of the individual diastereomeric bases, optionally repeating the process to obtain either one or both substantially free from the other; i.e., in a form having an optical purity of >95%. This separation can be performed before or after removal of any protecting group.
Wie gesagt, haben die Verbindungen dieser Erfindung eine Wirkung auf ein oder mehrere Enzyme, die Folsäure, und im besonderen metabolische Derivate der Folsäure, als Substrat verwenden. Die Verbindungen können unter der Aufsicht qualifizierter Personen verwendet werden, um das Wachstum von Neoplasmen, einschließlich Choriocarcinom, Leukämie, Adenocarcinom der weiblichen Brust, epidermale Hals-/Kopf- Tumoren, Plattenepithel- oder kleinzellige Lungentumore und verschiedene Lymphosarkome zu inhibieren. Die Verbindungen können ebenfalls zur Behandlung von Mycosis fungoides und Psoriasis eingesetzt werden.As stated, the compounds of this invention have an effect on one or more enzymes that use folic acid, and in particular metabolic derivatives of folic acid, as a substrate. The compounds can be used under the supervision of qualified persons to inhibit the growth of neoplasms including choriocarcinoma, leukemia, adenocarcinoma of the female breast, epidermal head/neck tumors, squamous cell or small cell lung tumors and various lymphosarcomas. The compounds can also be used to treat mycosis fungoides and psoriasis.
Die Verbindungen können oral verabreicht werden, werden aber vorzugsweise parenteral, allein oder in Kombination mit anderen therapeutischen Agenzien einschließlich anderen antineoplastischen Agenzien, Steroiden, usw., einem Säuger verabreicht, der an einem Neoplasma leidet und der Behandlung bedarf. Parenterale Wege der Verabreichung schließen intramuskuläre, intrathekale, intravenöse und intraarterielle mit ein. Die Dosierungsvorschrift muß entsprechend dem speziellen Neoplasma, dem Zustand des Patienten und der Wirkung eingestellt werden, aber im allgemeinen liegen die Dosen bei ungefähr 10 bis ungefähr 100 mg/Tag während 5-10 Tagen oder bei einer Einzeldosis pro Tag bei 250-500 mg in periodischen Abständen; zum Beispiel alle 14 Tage. Während eine geringe Toxizität verglichen mit anderen gegenwärtig in Gebrauch befindlichen anti-Metaboliten vorliegt, kann eine toxische Reaktion durch Reduzierung der täglichen Dosis, durch Verabreichung der Verbindung an jedem zweiten Tag oder durch längere Intervalle wie zum Beispiel 3 Tagen oder durch beide Maßnahmen gleichzeitig verhindert werden. Orale Verabreichungsformen schließen Tabletten und Kapseln ein, die 1-10 mg der Droge pro Dosierungseinheit beinhalten. Isotonische Salzlösungen, die 20-100 mg/ml enthalten, können zur parenteralen Verabreichung verwendet werden.The compounds may be administered orally, but are preferably administered parenterally, alone or in combination with other therapeutic agents including other antineoplastic agents, steroids, etc., to a mammal suffering from a neoplasm and requiring treatment. Parenteral routes of administration include intramuscular, intrathecal, intravenous, and intraarterial. The dosage regimen must be adjusted according to the specific neoplasm, the patient's condition, and the response, but generally doses are about 10 to about 100 mg/day for 5-10 days, or a single daily dose of 250-500 mg at periodic intervals; for example, every 14 days. While toxicity is low compared to other anti-metabolites currently in use, a toxic reaction can be prevented by reducing the daily dose, by administering the compound every other day or at longer intervals such as 3 days, or by both. Oral administration forms include tablets and capsules containing 1-10 mg of the drug per dosage unit. Isotonic saline solutions containing 20-100 mg/ml can be used for parenteral administration.
Die folgenden Beispiele sollen dazu dienen, die Erfindung weiter zu veranschaulichen. In den NMR-Daten bedeutet "s" Singlet, "d" bedeutet Doublet, "t" bedeutet Triplet, "q" bedeutet Quartet, "m" bedeutet Multiplet und "br" bedeutet einen breiten Peak.The following examples are intended to further illustrate the invention. In the NMR data, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet and "br" means broad peak.
Eine Mischung aus 1,94 g (6 mmol) 2-Pivaloylamino-4-hydroxy-6- brompyrido[2,3-d]pyrimidin, 1,6 g (6 mmol) Dimethyl-N-(hex-5- inoyl)-L-glutamat, 0,11 g Palladiumchlorid, 0,32 g Triphenylphosphin, 0,05 g Kupferiodid und 2,6 ml Triethylamin in 150 ml Acetonitril wurde unter Rückfluß während 3 Stunden erhitzt und dann auf Umgebungstemperaturen gekühlt. Das Lösungsmittel wurde unter reduziertem Druck entfernt und der Rückstand auf Silikagel mit 1:9 Methanol:Methylenchlorid chromatographiert, um Dimethyl-N-[6-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl)hex-5-inoyl]-L-glutamat zu erhalten, Schmelzpunkt 159-160ºC. Analytische Kalkulation für C&sub2;&sub5;H&sub3;&sub1;N&sub5;O&sub7;: C, 58,47; H, 6,08; N, 13,64. Gefunden: C, 58,23; H, 5,97; N, 13,43.A mixture of 1.94 g (6 mmol) 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine, 1.6 g (6 mmol) dimethyl N-(hex-5-inoyl)-L-glutamate, 0.11 g palladium chloride, 0.32 g triphenylphosphine, 0.05 g copper iodide and 2.6 ml triethylamine in 150 ml acetonitrile was heated under reflux for 3 hours and then cooled to ambient temperatures. The solvent was removed under reduced pressure and the residue chromatographed on silica gel with 1:9 methanol:methylene chloride to give dimethyl N-[6-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hex-5-inoyl]-L-glutamate, mp 159-160 °C. Analytical calculations for C 25 H 31 N 5 O 7 : C, 58.47; H, 6.08; N, 13.64. Found: C, 58.23; H, 5.97; N, 13.43.
In einer ähnlichen Weise kann durch Substitution einer äquivalenten Menge von Dimethyl-N-(hex-5-inoyl)-L-glutamat durch Dimethyl-N-(pent-4-inoyl)-L-glutamat im vorhergehenden Verfahren Dimethyl-N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl)pent-4-inoyl]-L-glutamat erhalten werden. In einem repräsentativen Experiment wurden folgende physikalische Konstanten für diese Verbindung erhalten: Schmelzpunkt 162- 163ºC. Analytische Kalkulation für C&sub2;&sub4;H&sub2;&sub9;N&sub5;O&sub7;: C, 57,71; H, 5,84; N, 14,02. Gefunden: C, 57,94; H, 5,72; N, 13,99.In a similar manner, by substituting an equivalent amount of dimethyl N-(hex-5-inoyl)-L-glutamate for dimethyl N-(pent-4-inoyl)-L-glutamate in the previous procedure, dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl)pent-4-inoyl]-L-glutamate can be obtained. In a representative experiment, the following physical constants were obtained for this compound: melting point 162-163°C. Analytical calculation for C24H29N5O7: C, 57.71; H, 5.84; N, 14.02. Found: C, 57.94; H, 5.72; N, 13.99.
Ebenso können aus Dimethyl-N-acryloyl-L-glutamat und Dimethyl- N-(but-3-inoyl)-L-glutamat sowohl Dimethyl-N-[3-(2- pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)acryloyl]-L- glutamat als auch Dimethyl-N-[4-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl)but-3-inoyl]-L-glutamat erhalten werden.Likewise, both dimethyl-N-[3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)acryloyl]-L-glutamate and dimethyl-N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)but-3-inoyl]-L-glutamate can be obtained from dimethyl-N-acryloyl-L-glutamate and dimethyl-N-(but-3-inoyl)-L-glutamate.
Durch Substitution einer äquivalenten Menge von Dimethyl-N- (hex-5-inoyl)-L-glutamat durch Dimethyl-N-(hept-6-enoyl)-L- glutamat im vorhergehenden Verfahren kann Dimethyl-N-[7-(2- pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hept-6- enoyl]-L-glutamat erhalten werden. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 79-81ºC. Analytische Kalkulation für C&sub2;&sub6;H&sub3;&sub5;N&sub5;O&sub7;: C, 58,01; H, 6,82; N, 13,53. Gefunden: C, 58,47; H, 6,48; N, 12,80.By substituting an equivalent amount of dimethyl N-(hex-5-inoyl)-L-glutamate for dimethyl N-(hept-6-enoyl)-L-glutamate in the preceding procedure, dimethyl N-[7-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hept-6-enoyl]-L-glutamate can be obtained. In a representative experiment, the following physical constants were obtained for this compound: melting point 79-81°C. Analytical calculation for C26H35N5O7: C, 58.01; H, 6.82; N, 13.53. Found: C, 58.47; H, 6.48; N, 12.80.
Dimethyl-N-(hex-5-inoyl)-L-glutamat kann durch Reaktion von 5- Hexinsäurechlorid (durch Behandlung von 5-Hexinsäure mit Thionylchlorid erhalten) mit Dimethyl-L-glutamat in Gegenwart eines Säureakzeptors, wie zum Beispiel Triethylamin, erhalten werden. 5-Hexinsäure kann ihrerseits durch, zum Beispiel, alkalische Hydrolyse von 5-Cyano-1-pentin hergestellt werden.Dimethyl-N-(hex-5-inoyl)-L-glutamate can be obtained by reaction of 5-hexyl chloride (by treatment of 5-hexyl acid with Thionyl chloride) with dimethyl-L-glutamate in the presence of an acid acceptor such as triethylamine. 5-Hexynic acid can in turn be prepared by, for example, alkaline hydrolysis of 5-cyano-1-pentyne.
Dimethyl-N-acryloyl-L-glutamat, Dimethyl-N-(pent-4-inoyl)-L- glutamat, Dimethyl-N-(but-3-inoyl)-L-glutamat und Dimethyl-N- (hept-6-enoyl)-L-glutamat werden auf ähnliche Weise aus den Säurechloriden der Acrylsäure, 4-Pentinsäure, 3-Butinsäure und 6-Heptensäure sowie aus Dimethyl-L-glutamat gewonnen.Dimethyl-N-acryloyl-L-glutamate, dimethyl-N-(pent-4-inoyl)-L-glutamate, dimethyl-N-(but-3-inoyl)-L-glutamate and dimethyl-N-(hept-6-enoyl)-L-glutamate are obtained in a similar way from the acid chlorides of acrylic acid, 4-pentinoic acid, 3-butyric acid and 6-heptenoic acid as well as from dimethyl-L-glutamate.
Zu einer Lösung aus 1,0 g Dimethyl-N-[6-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl)hex-5-inoyl]-L-glutamat in 20 ml Eisessig wurden 300 mg Platinoxid hinzugegeben. Die Mischung wurde unter einem Druck von einer Atmosphäre unter Rühren während 4 Stunden hydriert, der Katalysator durch Filtration entfernt und das Filtrat unter reduziertem Druck konzentriert. Chromatographie auf Silikagel, Elution mit 1:19 Methanol:Chloroform, ergab 0,84 g (82,7%) Dimethyl-N-[6-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)hexanoyl]-L-glutamat, Schmelzpunkt 162-166ºC. Analytische Kalkulation für C&sub2;&sub5;H&sub3;&sub9;N&sub5;O&sub7;: C, 57,57; H, 7,54; N, 13,43. Gefunden: C, 57,31; H, 7,25; N, 14,15.To a solution of 1.0 g of dimethyl N-[6-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hex-5-inoyl]-L-glutamate in 20 mL of glacial acetic acid was added 300 mg of platinum oxide. The mixture was hydrogenated under a pressure of one atmosphere with stirring for 4 hours, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Chromatography on silica gel, eluting with 1:19 methanol:chloroform, gave 0.84 g (82.7%) of dimethyl N-[6-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)hexanoyl]-L-glutamate, mp 162-166ºC. Analytical calculation for C25H39N5O7: C, 57.57; H, 7.54; N, 13.43. Found: C, 57.31; H, 7.25; N, 14.15.
In ähnlicher Weise wird aus Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d] pyrimidin-6-yl)pent-4-inoyl]-L-glutamat das Dimethyl-N-[5-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl)-L-glutamat hergestellt. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 151-159ºC. Analytische Kalkulation für C&sub2;&sub4;H&sub3;&sub7;N&sub5;O&sub7;: C, 56,79; H, 7,35; N, 13,80. Gefunden: C, 57,06; H, 7,22; N, 13,86.In a similar manner, dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)pent-4-inoyl]-L-glutamate is prepared to give dimethyl N-[5-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl)-L-glutamate. In a representative experiment, the following physical constants were obtained for this compound: Melting point 151-159ºC. Analytical calculation for C₂₄H₃₇N₅O₇: C, 56.79; H, 7.35; N, 13.80. Found: C, 57.06; H, 7.22; N, 13.86.
Ebenso werden Dimethyl-N-[3-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)propionyl-L-glutamat und Dimethyl-N-[4-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L-glutamat jeweils aus N-[3-(2-Pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl)acryloyl]-L-glutamat und Dimethyl-N-[4-(2- pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)but-3- inoyl]-L-glutamat hergestellt.Likewise, dimethyl N-[3-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)propionyl-L-glutamate and dimethyl N-[4-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L-glutamate are each prepared from N-[3-(2-pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl)acryloyl]-L-glutamate and dimethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)but-3-inoyl]-L-glutamate.
Durch Verwendung einer äquivalenten Menge von Dimethyl-N-[7-(2- pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hept-6- enoyl]-L-glutamat wird Dimethyl-N-[7-(2-pivaloylamino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl)heptanoyl]-L-glutamat erhalten. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 152-160ºC. Analytische Kalkulation für C&sub2;&sub6;H&sub4;&sub1;N&sub5;O&sub7;: C, 58,30; H, 7,72; N, 13,08. Gefunden: C, 58,51; H, 7,61; N, 12,87.By using an equivalent amount of dimethyl N-[7-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)hept-6-enoyl]-L-glutamate, dimethyl N-[7-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)heptanoyl]-L-glutamate is obtained. In a representative experiment, the following physical constants were obtained for this compound: melting point 152-160°C. Analytical calculation for C26H41N5O7: C, 58.30; H, 7.72; N, 13.08. Found: C, 58.51; H, 7.61; N, 12.87.
A. Fünf Gramm 2-Pivaloylamino-4-hydroxy-6-(4- carboxyphenylethinylpyrido[2,3-d]pyrimidin (in der Europäischen Patentanmeldung Nr. 87308921.3 beschrieben) und 1,60 g Platinoxid in 200 ml Trifluoressigsäure wurden in einem Parr- Apparat bei Umgebungstemperatur und 60 psi während 24 Stunden hydriert. Das Entfernen des Katalysators und die Konzentration des Filtrats ergab 2-Pivaloylamino-4-hydroxy-6-[2-(4- carboxycyclohex-1-yl)ethyl]-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin als einen weißen Festkörper, der weiterhin durch Säulenchromatographie (Waters 200), Elution mit 1:9 Methanol:Dichlormethan, gereinigt wurde. Schmelzpunkt 218- 234ºC. Analytische Kalkulation für C&sub2;&sub1;H&sub3;&sub2;N&sub4;O&sub4;: C, 63,35; H, 7,97; N, 13,85. Gefunden: C, 63,30; H, 7,48; N, 13,57.A. Five grams of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynylpyrido[2,3-d]pyrimidine (described in European Patent Application No. 87308921.3) and 1.60 g of platinum oxide in 200 mL of trifluoroacetic acid were hydrogenated in a Parr apparatus at ambient temperature and 60 psi for 24 hours. Removal of the catalyst and concentration of the filtrate gave 2-pivaloylamino-4-hydroxy-6-[2-(4-carboxycyclohex-1-yl)ethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine as a white solid which was further characterized by Column chromatography (Waters 200), eluting with 1:9 methanol:dichloromethane. Melting point 218-234ºC. Analytical calculations for C₂₁H₃₂N₄O₄: C, 63.35; H, 7.97; N, 13.85. Found: C, 63.30; H, 7.48; N, 13.57.
B. Zu einer Lösung aus 2,40 g 2-Pivaloylamino-4-hydroxy-6-[2- (4-carboxycyclohex-1-yl)ethyl]-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin in 50 ml trockenem N-Methylpyrrolidon und 2,25 ml N-Methylmorpholin wurden 2,75 g Phenyl-N- phenylphosphoaminochloridat hinzugefügt. Diese Mischung wurde bei 0ºC unter Stickstoff während 45 Minuten gerührt und der Rührvorgang wurde danach über 72 Stunden bei Umgebungstemperatur fortgesetzt. Das Lösungsmittel wurde durch Destillation bei 0,2mm/ 60ºC entfernt und der Rückstand auf Silikagel chromatographiert, Elution mit 1:19 Methanol:Chloroform, um 1,67 g (48%) Diethyl-N-[4-{2-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl}cyclohex-1-yl]-L-glutamat zu erhalten, Schmelzpunkt 160-170ºC. Analytische Kalkulation für C&sub3;&sub0;H&sub4;&sub7;N&sub5;O&sub7;: C, 61,10; H, 8,03; N, 11,87. Gefunden: C, 61,38; H, 7,90; N, 11,84.B. To a solution of 2.40 g of 2-pivaloylamino-4-hydroxy-6-[2- (4-carboxycyclohex-1-yl)ethyl]-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine in 50 mL of dry N-methylpyrrolidone and 2.25 mL of N-methylmorpholine was added 2.75 g of phenyl N-phenylphosphoaminochloridate. This mixture was stirred at 0 °C under nitrogen for 45 minutes and stirring was then continued for 72 hours at ambient temperature. The solvent was removed by distillation at 0.2 mm/60°C and the residue was chromatographed on silica gel, eluting with 1:19 methanol:chloroform to give 1.67 g (48%) of diethyl N-[4-{2-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl}cyclohex-1-yl]-L-glutamate, mp 160-170°C. Analytical calculation for C30H47N5O7: C, 61.10; H, 8.03; N, 11.87. Found: C, 61.38; H, 7.90; N, 11.84.
Eine Lösung aus o,5 g Dimethyl-N-[6-(2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)hexanoyl]-L- glutamat in 75 ml 1,0 N wässrigem Natriumhydroxid wird bei Raumtemperatur während 120 Stunden gerührt und der PH-Wert wird dann auf 7,0 durch vorsichtige Hinzugabe von 5,0 N Salzsäure eingestellt. Das Wasser wird unter reduziertem Druck entfernt und die konzentrierte Lösung dann in einem Eisbad gekühlt. Der so gebildete Festkörper wurde durch Filtration gesammelt und bei 80ºC getrocknet, um N-[6-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d)pyrimidin-6-yl)hexanoyl]-L-glutaminsäure zu ergeben, Schmelzpunkt Schaumbildung bei 135ºC Schmelzen bei 180-195ºC. NMR (DMSO-d&sub6;, 300 MHz) delta: 9,80 (s, br, 1H), 7,90 (s, J=8 Hz, 1H), 6,20 (s, 1H), 5,95 (s, 2H), 4,08 (m, 1H), 3,10 (m, 1H), 2,63 (t, J=10 Hz, 1H), 2,40 (m, 1H), 2,20 (t, J=8 Hz, 2H), 2,05 (t, J=8 Hz, 2H), 1,84 (m, 1H), 1,70 (m, 2H), 1,55 (m, 3H), 1,20 (m, 6H).A solution of 0.5 g of dimethyl N-[6-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)hexanoyl]-L-glutamate in 75 ml of 1.0 N aqueous sodium hydroxide is stirred at room temperature for 120 hours and the pH is then adjusted to 7.0 by careful addition of 5.0 N hydrochloric acid. The water is removed under reduced pressure and the concentrated solution is then cooled in an ice bath. The solid thus formed is collected by filtration and dried at 80 °C to give N-[6-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d)pyrimidin-6-yl)hexanoyl]-L-glutamic acid. to give, melting point foaming at 135ºC melting at 180-195ºC. NMR (DMSO-d6, 300 MHz) delta: 9.80 (s, br, 1H), 7.90 (s, J=8 Hz, 1H), 6.20 (s, 1H), 5.95 (s, 2H), 4.08 (m, 1H), 3.10 (m, 1H), 2.63 (t, J=10 Hz, 1H), 2.40 (m, 1H), 2.20 (t, J=8 Hz, 2H), 2.05 (t, J=8 Hz, 2H), 1.84 (m, 1H), 1.70 (m, 2H), 1.55 (m, 3H), 1.20 (m, 6H).
Aus Dimethyl-N-[5-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl]-L-glutamat wird in ähnlicher Weise N-[5-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl]-L- glutaminsäure hergestellt. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 144ºC (Erweichen und Schaumbildung); NMR (DMSO-d&sub6;, 300 MHz) delta: 9,70 (s, br, 1H), 8,01 (d, J=6 Hz, 1H), 6,17 (s, 1H), 5,88 (s, 2H), 4,13 (m, 1H), 3,17 (m, 1H), 2,68 (t, J=6 Hz, 1H), 2,42 (m, 1H), 2,22 (t, J=5 Hz, 2H), 2,07 (t, J=5 Hz, 2H), 1,88 (m, 1H), 1,70 (m, 2H), 1,44 (m, 3H), 1,24 (m, 4H).From dimethyl N-[5-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl]-L-glutamate is prepared in a similar manner to N-[5-(2-amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)pentanoyl]-L-glutamic acid. In a representative experiment, the following physical constants were obtained for this compound: melting point 144ºC (softening and foaming); NMR (DMSO-d6, 300 MHz) delta: 9.70 (s, br, 1H), 8.01 (d, J=6 Hz, 1H), 6.17 (s, 1H), 5.88 (s, 2H), 4.13 (m, 1H), 3.17 (m, 1H), 2.68 (t, J=6 Hz, 1H), 2.42 (m, 1H), 2.22 (t, J=5 Hz, 2H), 2.07 (t, J=5 Hz, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.44 (m, 3H), 1.24 (m, 4H).
N-[3-(2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)propionyl]-L-glutaminsäure und N-[4-(2-Amino- 4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl)butyryl]-L-glutaminsäure werden in analoger Weise aus Dimethyl-N-[3-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)propionyl]-L-glutamat beziehungsweise aus Dimethyl-N-[4-(2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L- glutamat hergestellt.N-[3-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)propionyl]-L-glutamic acid and N-[4-(2-amino- 4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L-glutamic acid are prepared analogously from dimethyl-N-[3-(2-pivaloylamino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)propionyl]-L-glutamate or from Dimethyl N-[4-(2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)butyryl]-L- glutamate was prepared.
In ähnlicher Weise wird N-[7-(2-Amino-4-hydroxy-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-6-yl)heptanoyl]-L- glutaminsäure aus Dimethyl-N-[7-(2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)heptanoyl]-L- glutamat hergestellt. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 185-195ºC (Schaumbildung). NMR (DMSO-d&sub6;, 300 MHz) delta: 9,68 (s, br, 1H), 8,01 (d, J=10 Hz, 1H), 6,20 (s, 1H), 5,88 (s, 2H), 4,14 (m, 1H), 3,10 (m, 1H), 2,66 (t, J=9 Hz, 1H), 2,35 (m, 1H), 2,20 (t, J=s Hz, 2H), 2,05 (t, J=5 Hz, 2H), 1,89 (m, 1H), 1,67 (m, 2H), 1,45 (m, 3H), 1,20 (m, 8H).Similarly, N-[7-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)heptanoyl]-L-glutamic acid is prepared from dimethyl N-[7-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)heptanoyl]-L-glutamate. In a representative experiment, the following physical constants were obtained for this compound: melting point 185-195ºC (foaming). NMR (DMSO-d₆, 300 MHz) delta: 9.68 (s, br, 1H), 8.01 (d, J=10 Hz, 1H), 6.20 (s, 1H), 5.88 (s, 2H), 4.14 (m, 1H), 3.10 (m, 1H), 2.66 (t, J=9 Hz, 1H), 2.35 (m, 1H), 2.20 (t, J=s Hz, 2H), 2.05 (t, J=5 Hz, 2H), 1.89 (m, 1H), 1.67 (m, 2H), 1.45 (m, 3H), 1.20 (m, 8H).
In analoger Weise wird bei Verwendung von Diethyl-N-[4-{2-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl}cyclohex-1-yl]-L-glutamat das N-[4-{2- (2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl)ethyl}cyclohex-1-yl]-L-glutaminsäure erhalten. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 210- 225ºC. NMR (DMSO-d&sub6;, 300 MHz) delta: 9,70 (s, br, 1H), 7,90 (m, 1H), 6,23 (s, 1H), 5,92 (s, 2H), 4,17 (m, 1H), 3,18 (m, 1H), 2,72 (t, J=9 Hz, 1H), 2,45 (m, 1H), 2,27 (t, J=6 Hz, 2H), 2,09 (m, 1H), 1,96 (m, 1H), 1,74 (m, 3H), 1,45 (m, 5H), 1,27 (m, 8H).In an analogous manner, using diethyl N-[4-{2-(2- pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl}cyclohex-1-yl]-L-glutamate, N-[4-{2- (2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl}cyclohex-1-yl]-L-glutamic acid is obtained. In a representative experiment, the following physical constants were obtained for this compound: melting point 210- 225ºC. NMR (DMSO-d6, 300 MHz) delta: 9.70 (s, br, 1H), 7.90 (m, 1H), 6.23 (s, 1H), 5.92 (s, 2H), 4.17 (m, 1H), 3.18 (m, 1H), 2.72 (t, J=9 Hz, 1H), 2.45 (m, 1H), 2.27 (t, J=6 Hz, 2H), 2.09 (m, 1H), 1.96 (m, 1H), 1.74 (m, 3H), 1.45 (m, 5H), 1.27 (m, 8H).
A. Eine Lösung aus 1,50 g (7,25 mmol) 5-Brom-2- thiophencarboxylsäure, mehrere Tropfen Dimethylformamid und 2,21 ml Thionylchlorid wurden unter Rückfluß während 2,5 Stunden erhitzt. Das Lösungsmittel wurde unter reduziertem Druck entfernt und der Rückstand in 10 ml trockenem Methylenchlorid erneut gelöst. Diese Lösung wurde tropfenweise zu einer eiskalten Lösung von 1,62 g Dimethyl-L-glutaminsäurehydrochlorid, 10 mg Dimethylaminopyrimidin und 2,11 ml Triethylamin in 25 ml trockenem Methylenchlorid hinzugefügt. Nach Beendigung der Zugabe wurde die Mischung bei Umgebungstemperatur während 12 Stunden gerührt, dann mit Wasser verdünnt und mit Methylenchlorid extrahiert. Die organischen Extrakte wurden mit 1,O N Salzsäure und gesättigter Natriumbikarbonatlösung gewaschen und dann evaporiert, um 2,71 g (100%) Dimethyl-N-[5- bromthien-2-ylcarbonyl]-L-glutamat als ein visköses Öl zu erhalten, das in dem folgenden Verfahren ohne weitere Aufreinigung verwendet werden kann.A. A solution of 1.50 g (7.25 mmol) of 5-bromo-2-thiophenecarboxylic acid, several drops of dimethylformamide and 2.21 mL of thionyl chloride was heated under reflux for 2.5 hours. The solvent was removed under reduced pressure and the residue was redissolved in 10 mL of dry methylene chloride. This solution was added dropwise to an ice-cold solution of 1.62 g of dimethyl-L-glutamic acid hydrochloride, 10 mg of dimethylaminopyrimidine and 2.11 mL of triethylamine in 25 mL of dry methylene chloride. After the addition was complete, the mixture was stirred at ambient temperature for 12 hours, then diluted with water and extracted with methylene chloride. The organic extracts were washed with 1,ON hydrochloric acid and saturated sodium bicarbonate solution and then evaporated to give 2.71 g (100%) of dimethyl N-[5-bromothien-2-ylcarbonyl]-L-glutamate as a viscous oil. which can be used in the following process without further purification.
Dimethyl-N-[5-bromfur-2-ylcarbonyl]-L-glutamat, ebenfalls ein visköses Öl, wird in analoger Weise aus 5-Brom-2- furancarboxylsäure hergestellt.Dimethyl N-[5-bromofur-2-ylcarbonyl]-L-glutamate, also a viscous oil, is prepared in an analogous manner from 5-bromo-2-furancarboxylic acid.
Dimethyl-N-(5-bromthien-3-ylcarbonyl)-L-glutamat kann in ähnlicher Weise aus 5-Brom-3-thienylcarboxylsäure hergestellt werden.Dimethyl N-(5-bromothien-3-ylcarbonyl)-L-glutamate can be prepared in a similar manner from 5-bromo-3-thienylcarboxylic acid.
B. Eine Mischung aus 1,70 g (6,32 mmol) 2-Pivaloylamino-4- hydroxy-6-ethinylpyrido[2,3-d]pyrimidin, 2,30 g (6,32 mmol) Dimethyl-N-(5-bromthien-2-yl-carbonyl)-L-glutamat, 44 mg Palladiumchlorid, 130 mg Triphenylphosphin, 25 mg Kupferoxid und 1,13 ml Triethylamin in 30 ml Acetonitril wurde unter Rückfluß während 3 Stunden erhitzt und dann auf Umgebungstemperatur gekühlt. Das Lösungsmittel wurde unter reduziertem Druck entfernt und der Rückstand einer Säulenchromatographie unterzogen, Elution mit 1:19 Methanol:Methylenchlorid, um Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl}ethinyl)thien-2-ylcarbonyl]-L-glutamat zu erhalten, Schmelzpunkt 228-230ºC. Analytische Kalkulation für C&sub2;&sub6;H&sub2;&sub7;N&sub5;O&sub7;S: C, 56,41; H, 4,92; N, 12,65; S, 5,79. Gefunden: C, 56,64; H, 4,77; N, 12,88; S, 5,58.B. A mixture of 1.70 g (6.32 mmol) of 2-pivaloylamino-4- hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 2.30 g (6.32 mmol) of dimethyl N-(5-bromothien-2-yl-carbonyl)-L-glutamate, 44 mg of palladium chloride, 130 mg of triphenylphosphine, 25 mg of copper oxide and 1.13 mL of triethylamine in 30 mL of acetonitrile was heated under reflux for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was subjected to column chromatography, eluting with 1:19 methanol:methylene chloride, to give dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl}ethynyl)thien-2-ylcarbonyl]-L-glutamate, mp 228-230 °C. Analytical calculation for C26H27N5O7S: C, 56.41; H, 4.92; N, 12.65; S, 5.79. Found: C, 56.64; H, 4.77; N, 12.88; S, 5.58.
In ähnlicher Weise kann durch Substitution einer äquivalenten Menge von Dimethyl-N-(5-bromthien-2-ylcarbonyl)-L-glutamat durch Dimethyl-N-(5-Bromfur-2-yl-carbonyl)-L-glutamat im vorhergehenden Verfahren Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl}ethinyl)fur-2-ylcarbonyl]-L- glutamat erhalten werden. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 135ºC (Dunkelfärbung), 181ºC (Zersetzung). Analytische Kalkulation für C&sub2;&sub6;H&sub2;&sub5;N&sub5;O&sub8;: C, 58,32; H, 4,71; N, 13,08. Gefunden: C, 58,58; H, 4,92; N, 13,11.Similarly, by substituting an equivalent amount of dimethyl N-(5-bromothien-2-ylcarbonyl)-L-glutamate for dimethyl N-(5-bromofur-2-ylcarbonyl)-L-glutamate in the previous procedure, dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl}ethynyl)fur-2-ylcarbonyl]-L-glutamate can be obtained. In a representative experiment, the following physical constants were obtained for this compound: melting point 135°C (dark color), 181°C (decomposition). Analytical calculation for C26H25N5O8: C, 58.32; H, 4.71; N, 13.08. Found: C, 58.58; H, 4.92; N, 13.11.
Ebenso kann durch Substitution einer äquivalenten Menge von Dimethyl-N-(5-bromthien-2-ylcarbonyl)-L-glutamat durch Dimethyl-N-(5-Bromthien-3-ylcarbonyl)-L-glutamat im vorhergehenden Verfahren Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl}ethinyl)thien-3-ylcarbonyl]- L-glutamat erhalten werden.Likewise, by substituting an equivalent amount of dimethyl-N-(5-bromothien-2-ylcarbonyl)-L-glutamate by dimethyl-N-(5-bromothien-3-ylcarbonyl)-L-glutamate in the previous process, dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl}ethynyl)thien-3-ylcarbonyl]- L-glutamate can be obtained.
Zu einer Lösung aus 0,5 g-Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl)ethinyl)thien-2-ylcarbonyl]- L-glutamat in 30 ml Eisessig wurden 1,5 g 5% Palladium auf Kohlenstoff hinzugefügt. Die Mischung wurde unter einem Druck von einer Atmosphäre unter Rühren über 18 Stunden hydriert. Der Katalysator wurde durch Filtration entfernt und das Filtrat unter reduziertem Druck konzentriert. Chromatographie auf Silikagel, Elution mit 1:19 Methanol:Chloroform, ergab 100 mg (19,7%) Dimethyl-N-[5-(2-{2-pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-yl-carbonyl]-L-glutamat und 204 mg (40,2%) des gewünschten Dimethyl-N-[5-(2-{2-pivaloylamino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)thien-2-ylcarbonyl]-L-glutamat, Schmelzpunkt 152- 160ºC. Analytische Kalkulation für C&sub2;&sub6;H&sub3;&sub5;N&sub5;O&sub7;S: C, 55,60; H, 6,28; N, 12,47. Gefunden: C, 55,76; H, 6,23; N, 12,26. Das teilweise hydrierte Nebenprodukt kann rehydriert werden, um zusätzliches Endprodukt zu erhalten.To a solution of 0.5 g of dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl)thien-2-ylcarbonyl]-L-glutamate in 30 mL of glacial acetic acid was added 1.5 g of 5% palladium on carbon. The mixture was hydrogenated under a pressure of one atmosphere with stirring for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Chromatography on silica gel, eluting with 1:19 methanol:chloroform, gave 100 mg (19.7%) of dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxypyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-yl-carbonyl]-L-glutamate and 204 mg (40.2%) of the desired dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamate, mp 152-160ºC. Analytical calculation for C26H35N5O7S: C, 55.60; H, 6.28; N, 12.47. Found: C, 55.76; H, 6.23; N, 12.26. The partially hydrogenated by-product can be rehydrogenated to yield additional final product.
In ähnlicher Weise wird aus Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-yl}ethinyl)fur-2-ylcarbonyl]-L- glutamat das Dimethyl-N-[5-(2-{2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d)pyrimidin-6-yl}ethyl)fur-2- ylcarbonyl]-L-glutamat hergestellt. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 155-162ºC; Analytische Kalkulation für C&sub2;&sub6;H&sub3;&sub3;N&sub5;O&sub8;: C, 57,45; H, 6,12; N, 12,88. Gefunden: C, 57,22; H, 6,08; N, 12,66.Similarly, dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)fur-2-ylcarbonyl]-L-glutamate is prepared from dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d)pyrimidin-6-yl}ethyl)fur-2-ylcarbonyl]-L-glutamate. In a representative experiment, the following physical constants were determined for this compound obtained: mp 155-162ºC; Analytical calculation for C₂₆H₃₃N₅O₈: C, 57.45; H, 6.12; N, 12.88. Found: C, 57.22; H, 6.08; N, 12.66.
Ebenso kann Dimethyl-N-[5-(2-{2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3- ylcarbonyl]-L-glutamat aus Dimethyl-N-[5-(2-pivaloylamino-4- hydroxypyrido[2,3-d]pyrimidin-6-ylethinyl)thien-3-ylcarbonyl]- L-glutamat hergestellt werden.Likewise, dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-3-ylcarbonyl]-L-glutamate can be prepared from dimethyl N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)thien-3-ylcarbonyl]- L-glutamate.
Eine Lösung aus 100 mg Dimethyl-N-[5-(2-{2-pivaloylamino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)thien-2-ylcarbonyl]-L-glutamat in 15 ml 1,0 N wässrigem Natriumhydroxid wird bei Raumtemperatur über 120 Stunden gerührt und dann der pH-Wert auf 7,0 durch vorsichtige Hinzugabe von 5,0 N Salzsäure eingestellt. Der sich bildende Festkörper wurde durch Filtration gesammelt und bei 80ºC getrocknet, um 61,5 mg (76,8%) N-[5-(2-{2-Amino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2- ylcarbonyl]-L-glutaminsäure zu erhalten, Schmelzpunkt 226- 240ºC. (Schaumbildung und Zersetzung). NMR (DMSO-d&sub6;, 300 MHz) delta: 9,80 (s, br, 1H), 8,45 (d, J=9 Hz, 1 H), 7,62 (d, J=3 Hz, 1H), 6,87 (d, J=3 Hz, 1H), 6,30 (s, 1H), 6,04 (s, 2H), 4,28 (m, 1H), 3,12 (m, 1H), 2,84 (m, 3H), 2,36 (m, 1H), 202 (m, 1H), 1,83 (m, 2H), 1,57 (m, 3H).A solution of 100 mg of dimethyl N-[5-(2-{2-pivaloylamino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)thien-2-ylcarbonyl]-L-glutamate in 15 mL of 1.0 N aqueous sodium hydroxide is stirred at room temperature for 120 hours and then the pH is adjusted to 7.0 by careful addition of 5.0 N hydrochloric acid. The resulting solid was collected by filtration and dried at 80°C to obtain 61.5 mg (76.8%) of N-[5-(2-{2-amino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2- ylcarbonyl]-L-glutamic acid, mp 226-240°C. (Foaming and decomposition). NMR (DMSO-d6, 300 MHz) delta: 9.80 (s, br, 1H), 8.45 (d, J=9 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 6.87 (d, J=3 Hz, 1H), 6.30 (s, 1H), 6.04 (s, 2H), 4.28 (m, 1H), 3.12 (m, 1H), 2.84 (m, 3H), 2.36 (m, 1H), 202 (m, 1H), 1.83 (m, 2H), 1.57 (m, 3H).
In ähnlicher Weise wird aus Dimethyl-N-[5-(2-{2-pivaloylamino- 4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)fur-2-ylcarbonyl]-L-glutamat die N-[5-(2-{2-Amino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)fur-2-ylcarbonyl]-L-glutaminsäure hergestellt. In einem repräsentativen Experiment wurden die folgenden physikalischen Konstanten für diese Verbindung erhalten: Schmelzpunkt 204-230ºC. (Schaumbildung). NMR (DMSO-d&sub6;, 300 MHz) delta: 9,80 (s, br, 1H), 8,27 (d, J=9 Hz, 1H), 7,03 (d, J=4 Hz, 1H), 6,30 (s, 1H), 6,25 (d, J=4 Hz, 1 H), 6,04 (s, 2H), 4,30 (m, 1H), 3,16 (m, 1H), 2,65 (m, 3H), 2,42 (m, 1H), 2,16 (t, J=7 Hz, 2H), 2,01 (m, 1H), 1,84 (m, 2H), 1,57 (m, 3H).Similarly, N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)fur-2-ylcarbonyl]-L-glutamic acid is prepared from dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- yl}ethyl)fur-2-ylcarbonyl]-L-glutamic acid. In a representative experiment, the following physical constants were obtained for this compound: Melting point 204-230ºC. (Foam formation). NMR (DMSO-d6, 300 MHz) delta: 9.80 (s, br, 1H), 8.27 (d, J=9 Hz, 1H), 7.03 (d, J=4 Hz, 1H), 6.30 (s, 1H), 6.25 (d, J=4 Hz, 1H), 6.04 (s, 2H), 4.30 (m, 1H), 3.16 (m, 1H), 2.65 (m, 3H), 2.42 (m, 1H), 2.16 (t, J=7 Hz, 2H), 2.01 (m, 1H), 1.84 (m, 2H), 1.57 (m, 3H).
N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-3-ylcarbonyl]-L-glutaminsäure kann in ähnlicher Weise aus Dimethyl-N-[5-(2-{2-pivaloylamino-4- hydroxy-5,6,7,8-tetrahydropyrido[2,3-d)pyrimidin-6- yl}ethyl)thien-3-ylcarbonyl]-L-glutamat hergestellt werden.N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-3-ylcarbonyl]-L-glutamic acid can be prepared in a similar manner from dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d)pyrimidin-6-yl}ethyl)thien-3-ylcarbonyl]-L-glutamate.
Der IC&sub5;&sub0; in ganzzelligen humanen Leukämiezellinien, CCRF-CEM, von N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure beträgt 0,0015 ug/m1. Der IC&sub5;&sub0; von N-[5-(2-{2-Amino-4-hydroxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)fur-2- ylcarbonyl]-L-glutaminsäure beträgt 0,010 ug/ml. Der IC&sub5;&sub0; von N-[4-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure beträgt 0,0756 ug/ml.The IC50 in whole cell human leukemia cell lines, CCRF-CEM, of N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid is 0.0015 ug/m1. The IC50 of N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)fur-2-ylcarbonyl]-L-glutamic acid is 0.010 ug/mL. The IC50 of N-[4-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid is 0.0756 ug/ml.
Die IC&sub5;&sub0; in ganzzelligen humanen Leukämiezellinien, CCRF-CEM, von anderen Verbindungen dieser Erfindung sind wie folgt: The IC50 in whole cell human leukemia cell lines, CCRF-CEM, of other compounds of this invention are as follows:
Die in vivo-Abschätzung gegen verschiedene Neoplasmen ergab folgende Werte: (a.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen: (IP, tägliche Verabreichung, 1 Tag) Dosis mg/kg % Inhibierung Toxizität (b.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen: (IP, tägliche Verabreichung, 10 Tage) Dosis mg/kg % Inhibierung Toxizität toxisch (c.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure B-16 Melanome in Mäusen (IP, tägliche Verabreichung, Tage 1, 7) Dosis mg/kg % Inhibierung Toxizität (d.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure C3H Mamma Adenocarcinome in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7, 10) Dosis mg/kg % Inhibierung Toxizität (e.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure CA-755 Adenocarcinome in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7, 10) Dosis mg/kg % Inhibierung Toxizität (f.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure CX-1 Colon Xenographie in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7, 10) Dosis mg/kg % Inhibierung Toxizität toxisch (g.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure LX-1 Lunge Xenographie in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7, 10) Dosis mg/kg % Inhibierung Toxizität toxisch (h.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutaminsäure MX-1 Mamma Xenographie in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7, 10) Dosis mg/kg % Inhibierung Toxizität toxisch (i.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-y}ethyl)fur-2-ylcarbonyl]-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen (IP, tägliche Verabreichung, acht Tage) Dosis mg/kg % Inhibierung Toxizität (j.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)fur-2-ylcarbonyl]-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen (IP, tägliche Verabreichung, Tage 1, 4, 7) Dosis mg/kg % Inhibierung Toxizität (k.) N-[4-(2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-ylbutyryl]-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen (IP, tägliche Verabreichung, acht Tage) Dosis mg/kg % Inhibierung Toxizität (l.) N-{4-[2-(2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl]cyclohexylcarbonyl}-L-glutaminsäure 6C3HED Lymphosarkome in Mäusen (IP, tägliche Verabreichung, acht Tage) Dosis mg/kg % Inhibierung ToxizitätThe in vivo assessment against various neoplasms gave the following values: (a.) N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid 6C3HED lymphosarcomas in mice: (IP, daily administration, 1 day) Dose mg/kg % Inhibition Toxicity (b.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid 6C3HED lymphosarcomas in mice: (IP, daily administration, 10 days) Dose mg/kg % Inhibition Toxicity toxic (c.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid B-16 Melanoma in mice (IP, daily administration, days 1, 7) Dose mg/kg % Inhibition Toxicity (d.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid C3H Mammary Adenocarcinomas in Mice (IP, daily administration, days 1, 4, 7, 10) Dose mg/kg % Inhibition Toxicity (e.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid CA-755 Adenocarcinomas in mice (IP, daily administration, days 1, 4, 7, 10) Dose mg/kg % Inhibition Toxicity (f.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid CX-1 Colon Xenography in mice (IP, daily administration, days 1, 4, 7, 10) Dose mg/kg % Inhibition Toxicity toxic (g.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid LX-1 Lung Xenography in mice (IP, daily administration, days 1, 4, 7, 10) Dose mg/kg % Inhibition Toxicity toxic (h.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid MX-1 Mammary Xenography in mice (IP, daily administration, days 1, 4, 7, 10) Dose mg/kg % Inhibition Toxicity toxic (i.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-y}ethyl)fur-2-ylcarbonyl]-L-glutamic acid 6C3HED lymphosarcomas in mice (IP, daily administration, eight days) Dose mg/kg % Inhibition Toxicity (j.) N-[5-(2-{2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl}ethyl)fur-2-ylcarbonyl]-L-glutamic acid 6C3HED lymphosarcomas in mice (IP, daily administration, days 1, 4, 7) Dose mg/kg % Inhibition Toxicity (n.) N-[4-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-ylbutyryl]-L-glutamic acid 6C3HED lymphosarcomas in mice (IP, daily administration, eight days) Dose mg/kg % Inhibition Toxicity (l.) N-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-6-yl)ethyl]cyclohexylcarbonyl}-L-glutamic acid 6C3HED lymphosarcomas in mice (IP, daily administration, eight days) Dose mg/kg % Inhibition Toxicity
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| US4684653A (en) * | 1985-03-08 | 1987-08-04 | The Trustees Of Princeton University | Pyrido(2,3-d)pyrimidine derivatives |
| ZA861235B (en) * | 1985-03-08 | 1986-10-29 | Univ Princeton | Pyrido(2,3-d)pyrimidine derivatives |
| NZ219971A (en) * | 1986-06-06 | 1989-08-29 | Univ Princeton | Tetrahydropyrido (2,3-d pyrimidine derivatives and pharmaceutical compositions |
| IE60038B1 (en) * | 1986-06-30 | 1994-05-18 | Univ Princeton | 4(3H)-oxo-5, 6, 7, 8-tetrahydropyrido-[2, 3-d]pyrimidine derivatives |
-
1989
- 1989-05-02 DK DK198902152A patent/DK172753B1/en not_active IP Right Cessation
- 1989-05-03 IL IL9017989A patent/IL90179A/en not_active IP Right Cessation
- 1989-05-04 EP EP89304499A patent/EP0343801B1/en not_active Expired - Lifetime
- 1989-05-04 AT AT89304499T patent/ATE109480T1/en not_active IP Right Cessation
- 1989-05-04 DE DE68917211T patent/DE68917211T2/en not_active Expired - Fee Related
- 1989-05-04 ES ES89304499T patent/ES2057116T3/en not_active Expired - Lifetime
- 1989-05-17 CA CA000599937A patent/CA1340631C/en not_active Expired - Fee Related
- 1989-05-23 PT PT90635A patent/PT90635B/en not_active IP Right Cessation
- 1989-05-23 NZ NZ229242A patent/NZ229242A/en unknown
- 1989-05-24 AU AU35109/89A patent/AU611027B2/en not_active Ceased
- 1989-05-24 RU SU894614259A patent/RU2002747C1/en active
- 1989-05-25 KR KR1019890007041A patent/KR0131589B1/en not_active IP Right Cessation
- 1989-05-25 HU HU892684A patent/HU205356B/en not_active IP Right Cessation
- 1989-05-25 CN CN89103686A patent/CN1025334C/en not_active Expired - Fee Related
- 1989-05-25 JP JP1132541A patent/JP2818198B2/en not_active Expired - Lifetime
- 1989-06-12 IE IE176789A patent/IE63620B1/en not_active IP Right Cessation
-
1997
- 1997-09-24 HK HK97101830A patent/HK1000284A1/en not_active IP Right Cessation
-
1998
- 1998-06-12 CY CY9802055A patent/CY2055B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1025334C (en) | 1994-07-06 |
| DK215289A (en) | 1989-11-26 |
| DK172753B1 (en) | 1999-06-28 |
| ATE109480T1 (en) | 1994-08-15 |
| HUT50342A (en) | 1990-01-29 |
| PT90635A (en) | 1989-11-30 |
| JP2818198B2 (en) | 1998-10-30 |
| IE891767L (en) | 1989-11-25 |
| AU3510989A (en) | 1989-11-30 |
| CY2055B1 (en) | 1998-06-12 |
| KR900018100A (en) | 1990-12-20 |
| HK1000284A1 (en) | 1998-02-20 |
| RU2002747C1 (en) | 1993-11-15 |
| KR0131589B1 (en) | 1998-04-17 |
| PT90635B (en) | 1994-10-31 |
| EP0343801A2 (en) | 1989-11-29 |
| IE63620B1 (en) | 1995-05-17 |
| IL90179A0 (en) | 1989-12-15 |
| JPH0267281A (en) | 1990-03-07 |
| EP0343801B1 (en) | 1994-08-03 |
| CN1038098A (en) | 1989-12-20 |
| ES2057116T3 (en) | 1994-10-16 |
| DK215289D0 (en) | 1989-05-02 |
| CA1340631C (en) | 1999-07-06 |
| EP0343801A3 (en) | 1991-05-02 |
| HU205356B (en) | 1992-04-28 |
| NZ229242A (en) | 1990-10-26 |
| DE68917211D1 (en) | 1994-09-08 |
| IL90179A (en) | 1994-02-27 |
| AU611027B2 (en) | 1991-05-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |